ALCOHOL INTAKE AND RETINOID METABOLISM AND SIGNALING

简介(申请人提供)：我们的长远目标是研究 _ 维甲酸对慢性过度饮酒的化学预防作用 肝脏和外周器官的癌变。目前的拨款建议 专注于细胞增殖，这在肝脏中起着核心作用 起始和促进阶段的致癌作用，特别是当 化学致癌物也参与其中。维甲酸在 控制多种癌症的致癌进展，包括肝癌 癌症。维甲酸的化学预防作用之一被认为是 通过延缓损伤进展来控制增殖 细胞进入S期，这允许DNA修复和诱导细胞凋亡， 从而降低致癌的风险。然而，从长远来看， 过量的乙醇摄入会降低肝脏的维甲酸水平。观察到的是 维甲酸在血浆和癌肝中的浓度均降低 肝癌患者的组织，提示维甲酸耗竭在 肝癌的发生。然而，目前尚不清楚1)慢性 乙醇诱导的肝细胞增殖(这可以将肝细胞 从对致癌物的抵抗状态到敏感状态)是由于 与酒精损害的视黄醇代谢和信号有关，如果是这样，2)是否 通过抑制乙醇诱导的视黄醇来恢复视黄醇状态 分解代谢或补充维甲酸可抑制乙醇诱导的 细胞过度增殖和乙醇促进(二乙基亚硝胺 诱导)肝细胞癌的发生。 我们将研究视黄醇信号和/或减弱的可能作用 Jun氨基末端依赖蛋白激酶(JNK)信号的上调 慢性乙醇处理对酒精诱导的肝细胞的作用途径 增殖和酒精促进的肝细胞癌变 (二乙基亚硝胺诱导)。同时，我们将测试是否有治疗 氯甲唑(一种维甲酸分解代谢的抑制剂)和 全反式维甲酸对酒精诱导的大鼠酒精损伤的抑制作用 肝细胞增殖与酒精促进的肝细胞 通过恢复正常的视黄醇信号和/或抑制致癌 JNK依赖的信号通路。 这项研究将首次将维甲酸信号的调节与 Jun氨基末端依赖的蛋白激酶途径与细胞增殖和凋亡 一种酒精处理、化学诱导致癌的动物模型，它将 对预防和治疗与酒精相关的人类具有重要意义 癌症。

DESCRIPTION (provided by applicant): Our long-term objective is to study the +___________________________________ chemopreventive effect of retinoids on chronic and excessive alcohol related carcinogenesis in the liver and peripheral organs. The present grant proposal focuses on cell proliferation, which plays a central role in hepatic carcinogenesis in both the initiation and promotion stages, particularly when chemical carcinogens are involved. Retinoic acid plays an important role in controlling carcinogenic progression in a variety of cancers, including liver cancer. One of the chemopreventive effects of retinoids is thought to be mediated through control of proliferation via delaying progression of damaged cells into S phase, which allows for DNA repair and induction of apoptosis, thereby reducing the risk of carcinogenic initiation. However, long term and excessive ethanol intake reduces hepatic retinoid levels. The observation that retinoid concentrations are decreased in both plasma and cancerous liver tissues of hepatocarcinoma patients, suggests a role for retinoid depletion in hepatocarcinogenesis. However, it is not known 1) whether chronic ethanol-induced hepatocellular proliferation (which could convert hepatocytes from a state of resistance to a carcinogen to a state of susceptibility) is due to alcohol-impaired retinoid metabolism and signaling, and if so, 2) whether restoration of retinoid status by either inhibiting ethanol-induced retinoid catabolism or supplementing retinoic acid can suppress both ethanol-induced cell hyperproliferation as well as ethanol-promoted (diethylnitrosamine induced) hepatocellular carcinogenesis. We will investigate the possible role of diminished retinoid signaling and/or the up-regulation of the Jun N-terminal kinases-dependent (JNK) signaling pathway by chronic ethanol treatment on alcohol induced hepatocellular cell proliferation as well as alcohol-promoted hepatocellular carcinogenesis (induced by diethylnitrosamine). Simultaneously, we will test whether treatment with either chlormethiazole (an inhibitor of retinoic acid catabolism) and all-trans retinoic acid in ethanol-fed rats can inhibit alcohol-induced hepatocellular cell proliferation as well as alcohol-promoted hepatocellular carcinogenesis via either restoring normal retinoid signaling and/or inhibiting the JNK dependent signaling pathway. This study will be the first to link the regulation of retinoid signaling with Jun N-terminal kinases-dependent pathway, cell proliferation and apoptosis in an alcohol-treated, chemically induced carcinogenesis animal model, which would have implications for the prevention and treatment of alcohol related human cancers.